Category: Drug Target Strategies
Epstein-Barr virus (EBV) latently infects more than 90% of adults. Latent EBV infection has been associated with both Hodgkin’s and non-Hodgkin’s lymphomas, including Burkitt’s lymphoma (BL). Overexpression of the oncogenic protein MYC is observed in BL and various other cancers. In the case of BL, MYC overexpression is the result of a translocation that allows MYC to be expressed under an immunoglobulin (Ig) promoter. Transgenic mice constitutively expressing both human MYC (under the Igλ locus) and EBV-encoded latent membrane protein 2A (LMP2A), which is observed in EBV-positive BL, develop tumors significantly faster than mice only overexpressing MYC. These mice (LMP2A/λ-MYC) have a significantly higher percentage of pre-tumor, splenic B-cells in the S and G2/M phases of the cell cycle than do λ-MYC mice, suggesting that the expression of LMP2A enhances MYC-induced cell-cycle progression.
Previous research has shown that protein levels (but not mRNA levels) of the cell-cycle inhibitor p27 are lower in tumors from LMP2A/λ-MYC mice than λ-MYC mice. Typically, p27 degradation occurs in the cytoplasm following phosphorylation at serine 10. λ-MYC mice homozygously expressing an S10A knock-in of p27 (p27[S10A/S10A]) display a decrease in cell cycle progression from G1 to S phase in pre-tumor splenic B cells. LMP2A/λ-MYC mice carrying the S10A mutation, however, showed no such reduction in cell-cycle progression.
Another method of p27 degradation is mediated by the SCF[Skp2] complex, which requires the activity of Cks1. Our studies show that Cks1-null LMP2A/λ-MYC mice (LMP2A/λ-MYC/Cks1[-/-]) exhibit a reduction in G1-S transition of pre-tumor splenic B cells and a partial but significant delay in tumor onset. In the present study, we prevent both pathways of p27 degradation with the creation of LMP2A/λ-MYC/Cks1[-/-]/p27[S10A/S10A] mice. This genotype delays tumor onset much more dramatically than the Cks1 knockout by itself. Pre-tumor splenic B cells from LMP2A/λ-MYC/Cks1[-/-]/p27[S10A/S10A] mice also display significantly decreased G1-S phase cell cycle progression. These data show that a loss of SCF[Skp2]-mediated p27 degradation combined with nuclear localization of p27 by expression of the S10A knock-in is the most effective method yet for preventing tumor growth in our LMP2A/λ-MYC model of lymphoma. We hypothesize that LMP2A signaling promotes the degradation of p27 by both of these pathways.
Determining the mechanism by which LMP2A signaling leads to p27 degradation in LMP2A/MYC-driven lymphoma can lead to targeted therapies aimed at maintaining normal p27 levels in BL patients. Identifying additional genes involved in tumor development in our LMP2A/λ-MYC model compared to our λ-MYC model can also lead to the discovery of new therapeutic targets in BL treatment.
Richard Sora– Graduate Student, Northwestern University, Chicago, IL
Richard attended the University of Illinois at Urbana-Champaign for his undergraduate studies. There, he majored in Biology in the Integrative Biology Honors (IBH) concentration, and minored in Chemistry. Richard joined the lab of Dr. Mary Schuler, where he performed research that led to his undergraduate thesis project, which allowed him to graduate with "High Distinction." He also performed a summer of research through Northwestern University's Summer Research Opportunity Program in the Lab of Dr. Vladimir Gelfand. Upon graduating from the University of Illinois, Richard entered Northwestern to pursue his PhD in the Driskill Graduate Program in Life Sciences. He is currently in his fourth year and is conducting his thesis research in the Lab of Dr. Richard Longnecker, where he is studying the link between Epstein-Barr virus and lymphoma. Richard also completed the "Management for Scientists and Engineers" program at Northwestern's Kellogg Business School.